PROJECT SUMMARY/ABSTRACT Obstructive Sleep Apnea (OSA) is a prevalent disorder with a number of adverse cardiovascular and neurocognitive consequences. However, the leading treatment, positive airway pressure (PAP), is poorly toler- ated by many individuals and thus the development new treatment strategies are critically needed. Several studies indicate that the pharyngeal airway obstructs at different sites in different patients (pal- ate, tongue, lateral walls, epiglottis). While a number of new site-specific devices and surgeries available for treating OSA, they cannot be utilized with maximum effectiveness because the site of airway collapse is diffi- cult to identify in sleeping humans without invasive testing. Consequently, the devices/surgeries are oftentimes administered to the wrong patient and thus do not produce the desired effect. The field, therefore, would great- ly benefit from a simple clinical method for determining the site of pharyngeal collapse. In Aim 1 of this grant, we propose a potential solution to this problem. We hypothesize that the obstructed flow limitation shape will provide structural information about the site of pharyngeal collapse. For example, flow parameters such as the amount of negative effort dependence, fluttering (snoring), expiratory mouth leaking, and sharp discontinuities could provide clues to the underlying mechanisms and site of collapse that inform treatment decisions. Another potential problem hindering the successful use of non-PAP therapies is that they have a limited effect size on airway patency, e.g., the mandible can only be advanced so far forward, or only so much tissue can be surgically excised. Hence, these treatments are less effective in patients with a severely collapsible pharynx, even (potentially) if they are correctly matched with the structure causing collapse. Therefore, know- ing the anatomical predisposition to pharyngeal collapse is also an important criterion for patient selection for non-PAP therapies. Again, however, the collapsibility of the upper airway cannot be measured without special- ized physiological procedures. Therefore, Aim 2 seeks to identify a method for estimating collapsibility from clinically available data, namely the airflow rate during sleep. The main hypothesis is that a large drop in airflow from wakefulness to sleep (e.g., complete apneas) signifies a highly collapsible airway, whereas a small drop in airflow from wakefulness to sleep (e.g., RERAs or ?shallow? hypopneas) signifies a less collapsible airway. Lastly, in Aim 3 we will use the structural and collapsibility information gained by the airflow analyses described above to predict the response to two of the most common alternative treatments for OSA, oral appli- ances and uvulopalatopharyngoplasty The results could lead to (much needed) better predictors for these im- portant therapies. In addition, the proposed methodologies could, in the future, be extended to other non-PAP treatments, such as targeted pharyngeal surgeries, drug therapy to activate pharyngeal muscles, hypoglossal nerve stimulation, oropharyngeal pressure therapy, etc.